Reactivation of mutant p53 has emerged as a promising approach for cancer therapy. Recent studies have identified several mutant p53-reactivating compounds that target thiol groups in mutant p53. Here we have investigated the relationship between thiol reactivity, p53 thermostabilization, mutant p53 refolding, mutant p53-dependent growth suppression, and induction of cell death. Analysis of the National Cancer Institute database revealed that Michael acceptors show the highest selectivity for mutant p53-expressing cells among analyzed thiol-reactive compounds. Further experimental testing demonstrated that Michael acceptors, aldehydes, imines, and primary alcohols can promote thermodynamic stabilization of mutant p53. Moreover, mild thiol reactivity, often coupled with combined chemical functional groups, such as in imines, aldehydes, and primary alcohols, can stimulate mutant p53 refolding. However, strong electrophile activity was associated with cellular toxicity. Our findings may open possibilities for rational design of novel potent and selective mutant p53-reactivating compounds.

中文翻译：

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硫醇反应性对靶向突变体p53的作用

突变体p53的重新激活已成为一种有前途的癌症治疗方法。最近的研究已经确定了几种针对突变p53的巯基的突变p53活化化合物。在这里，我们研究了硫醇反应性，p53热稳定，突变体p53折叠，突变体p53依赖性生长抑制和诱导细胞死亡之间的关系。对美国国家癌症研究所数据库的分析表明，在分析的硫醇反应性化合物中，迈克尔受体对表达突变型p53的细胞显示出最高的选择性。进一步的实验测试表明，迈克尔受体，醛，亚胺和伯醇可以促进突变体p53的热力学稳定。此外，适度的硫醇反应性通常与结合的化学官能团（例如亚胺，醛，和伯醇，可以刺激突变型p53的重新折叠。但是，强亲电活性与细胞毒性有关。我们的发现可能为合理设计新型有效且选择性的突变型p53激活化合物开辟可能性。